Introduction

Beta-2 adrenergic agonists are a drug class used as mainstay treatments for respiratory diseases such as bronchial asthma and chronic obstructive pulmonary disease (COPD). They replicate the functions of catecholamines such as epinephrine, norepinephrine, and dopamine in producing different autonomic responses within the body. Specifically, the smooth muscle of the airway, uterus, intestine, and systemic vasculature are areas where beta-2 agonists have the greatest effect. Thus, the focus of development for this drug class has been mostly on the clinical implications involving their ability to affect those target organ systems. Within the last century, there has been extensive research on the bronchodilatory as well as the anti-bronchoconstrictive properties of these drugs.

The early 1900s marked the advent of epinephrine as a form of treatment in Western medicine after successfully obtaining it from the adrenal gland; this became the treatment for asthmatic patients until its replacement in the 1940s with the formulation of isoproterenol, a non-selective beta-adrenoreceptor agonist. However, the adverse side effects of isoproterenol became an issue of concern, and the search continued for a treatment with a better side effect profile. With the discovery of the alpha-1, alpha-2, beta-1, beta-2 receptors in subsequent years, it became known that airway bronchodilation had a strong correlation specifically with beta-2 receptors in the lung vasculature. Pharmacological pursuits turned towards maximizing the selectivity towards the beta-2 receptor in an attempt to reduce the incidence of adverse side effects of the non-selective isoproterenol. These new drugs, classified as beta-2 adrenergic receptor agonists, have since become frontline treatments for bronchial asthma and chronic obstructive pulmonary disease (COPD). Subsequent research continues to aim at improving the efficacy, minimizing adverse effects, with the goal to decrease symptoms, mortality rates, and improve patient quality of life.[1] However, since the discovery of beta-2 agonists, there have been many discussions regarding the potential long-term risks versus benefits to the overall rate of morbidity and mortality. This article aims to provide a foundational background of the mechanism of action of beta-2 agonist, the various classifications and their associated clinical significance as well as discuss areas of concern and speculations regarding this class of medications.

Function

Mechanism of action:

Circulating catecholamines activate adrenergic receptors as part of our functional autonomic system to produce parasympathetic and sympathetic physiological responses. Mimicking catecholamines, beta-2 agonists act as ligands to adrenergic receptors with increased selectivity towards beta-2 adrenergic receptors. The activation of the beta-2 adrenergic receptor initiates a transmembrane signal cascade which involves the heterotrimeric G protein, Gs, and the effector, adenylyl cyclase. Adenylyl cyclase then increases intracellular cAMP via the hydrolysis of ATP. The elevated cAMP concentration serves to activate cAMP-dependent protein kinase A (PKA). PKA can phosphorylate intracellular substrates, which modulate various effects within the cell. Specifically, in airway smooth muscle, PKA acts to phosphorylate Gq-coupled receptors leading to a cascade of intracellular signals which have been proposed to reduce intracellular Ca2+ or decrease the sensitivity of Ca2+.[1] The change in Ca2+ results in the inhibition of myosin light chain phosphorylation, subsequently preventing airway smooth muscle contraction. This action is the underlying mechanism behind beta-2 agonists, which promotes the bronchodilatory effects used to treat many common respiratory diseases. There have been proposals that beta-2 agonists also provide anti-inflammatory effects within the airway smooth muscle through the reduction of intercellular adhesion molecule-1, the reduction of granulocyte-macrophage colony-stimulating factors release, stabilization of mast cell degranulation, and through the inhibition of multiple inflammatory pathways.[2]

Classification:

Their onset of action and duration determines the classification of beta-2 agonists. The classes separate into short-acting beta agonists (SABAs), long-acting beta agonists (LABAs), and most recently, ultra-long-acting beta agonists (ultra-LABAs). As the names suggest, SABAs have the shortest half-life and are for immediate symptomatic relief. LABAs, along with ultra-LABAs, provide prolonged, sustained treatment due to their increased half-life. The different properties between these classes occur through modifications of the molecular structure of the drugs. For example, the prolonged duration is achievable by decreasing the susceptibility of the beta-2 agonists to catechol O-methyl transferase (COMT) and monoxidase enzymes that induce oxidative deamination and methylation, thereby inactivating the beta-2 agonist.

SABAs

SABAs are the first-line medications for acute treatment in asthma symptoms and exacerbations. They are also commonly used in conjunction with LABAs, inhaled corticosteroids, or long-acting muscarinic agonists in treatment for COPD. Typical administration of these agents is as inhaled substances via metered dosing or dry powder inhalation. Compared to the alternative oral administration, inhalation has an increase in therapeutic value, as well as a decrease in systemic side effects.[2] The hallmark SABA is the drug salbutamol, which has an onset of action of under 5 minutes, and a therapeutic effect duration between 3 to 6 hours. While most commonly used as airway treatment, nebulized albuterol is also useful as a treatment for hyperkalemia by providing a rapid shift of intracellular potassium.[3] Terbutaline is a commonly used short-acting beta-2 agonist as a tocolytic in the cessation of labor contractions.

Common SABAs:

Salbutamol (albuterol)

Terbutaline

Levalbuterol

Pirbuterol

LABAs

LABAs are used in treatment for patients with asthma and COPD as well, often in conjunction with inhaled corticosteroids given there is evidence of greater efficacy with dual therapy versus monotherapy LABA.[4] They have an onset of duration greater than 5 minutes compared to the SABAs, with up to 15 minutes for salmeterol, and duration of effect for at least 12 hours. Similar to SABAs, the recommended route of administration for LABAs is through inhalation. LABAs are generally added on as second-line treatment in asthma that has failed symptomatic relief with SABAs and ICS. However, there is current controversy on the use of LABA as monotherapy versus dual therapy with ICS, as will be discussed in the topics further below.

Common LABAs:

Salmeterol

Formoterol

Ultra-LABAs

Ultra-LABAs have the greatest duration of effect, up to 24 hours, and they have the additional benefit of being a once a day treatment dosage. Indacaterol has been FDA approved as maintenance treatments for patients with COPD in combination with other bronchodilators. Indacaterol administration is as a dry powder with an onset of action around 5 minutes. Many other ultra-LABAs are currently undergoing research as well, with the potential to provide improvement to compliance and convenience compared to the current options of asthma and COPD treatments.[5]

Common ultra-LABAS:

Indacaterol

Olodaerol

Vilanterol

Formoterol

Administration:

The major routes of administration for beta-2 agonists include metered dosed-inhalers, nebulizers, dry powder inhalers, orally, subcutaneously, or intravenously. The preferred route of administration for beta-2 agonists in the treatment of asthma and COPD is through inhalation. Inhalation localizes the drug to the lung tissue, concentrating the therapeutic effect to the airway smooth muscles while minimizing the distribution of the drug to the systemic circulation. There has been no correlation between the therapeutic effect of inhaled beta-2 agonists and the peak plasma levels of the beta-2 agonist.[6] Less frequently, beta-2 agonists are given orally, which have been shown to cause an increase in systemic side effects. The tocolytic terbutaline can also be given IV, IM, or orally.

Issues of Concern

Adverse effects:

Adverse effects of beta-2 agonists most commonly involve the desensitization of the beta-2 adrenergic receptor to the beta-2 agonist. Due to the similar properties between the classes of adrenergic receptors, beta-2 agonists can create an “off-target” effect in stimulating either alpha-1, alpha-2, or beta-1 receptors.[7] Most common side effects of beta-2 agonists involve the cardiac, metabolic, or musculoskeletal system.

Due to the vasodilatory effect of peripheral vasculature and subsequent decrease in cardiac venous return, compensatory mechanisms manifest as tachycardia are relatively common, especially within the first weeks of usage. Cardiac toxicity in the form of arrhythmias, cardiomyopathy, and ischemia have been correlated more strongly with older generation beta-2 agonists according to multiple reports ranging from single case reports to case-control studies.[8]

Arrhythmias are seen more commonly in fenoterol usage versus albuterol, and arrhythmias have an increase in frequency in patients with underlying heart disease or concomitant theophylline use.[9] Beta-2 agonists have been shown to decrease serum potassium levels via an inward shift of potassium into the cells due to an effect on the membrane-bound Na/K-ATPase, which can potentially result in hypokalemia. Beta-2 agonists also promote glycogenolysis, which can lead to inadvertent elevations in serum glucose. Musculoskeletal tremors are a potential side-effect as well, found more commonly with the use of oral beta-2 agonists.

The degree of which these adverse effects precipitate is generally associated with factors such as the selectivity ability of each beta-2 agonist to its respective receptor and the medication dosages. Several studies have also indicated hypoxemia and hypercapnia as exacerbating factors to the cardiotoxic effects of beta-2 agonists.[7]

Tolerance:

Desensitization of the beta-2 agonist receptor due to prolonged stimulation from agonists can lead to tolerance. Tolerance involves the blunting of both the bronchodilatory and the anti-bronchoconstrictor effects of beta-2 agonists.[10] Multiple studies have reproduced a reduction in anti-bronchoconstriction from extended use of salbutamol after clinical induction of airway constriction with a methacholine test.[11] However, clinical implications of tolerance in affecting the management of treatment are still under investigation. Theoretically, LABAs should result in increased tolerance compared to SABAs due to the continuous beta receptor stimulation produced from their prolonged duration of action. However, this remains a topic of speculation, as studies have shown varying degrees of tolerance between both SABAs and LABAs.[12][13] Research has also suggested multiple external factors as influences of the degree of beta-2 agonist tolerance, including genetic polymorphisms of the beta-2 receptor, the degree of airway inflammation, and the route of medication delivery.[14]

Clinical Significance

Asthma and COPD are currently amongst the most prevalent respiratory diseases in the population. In a randomized study in Italy involving 3000 subjects on the prevalence of asthma and COPD, the study concluded one in eight adults age greater than 20 years old were affected by either asthma, COPD, or the co-existence of both diseases.[15] Treatment and management begin with understanding the symptoms, confirmatory diagnostic tests, and proper assessment of the severity of the conditions. Beta-2 agonists are an integral part of the frontline management for symptomatic control, prevention of exacerbations, and improving quality of life. The National Asthma Education and Protection Program has integrated a step-wise approach to the treatment of bronchial asthma with SABAs as the first line for mild acute episodes. Stratification on the severity of asthma has its basis on the frequency of daytime and nighttime symptoms, the degree of interference to normal activity, and the lung function measured by the forced expiratory volume (FEV1) and FEV1/forced vital capacity (FVC). A moderate or severe persistent asthma warrants additional therapy in the form of inhaled corticosteroids followed by LABAs. Additional respiratory therapies are a consideration if symptoms persist or worsen. Similarly, the Global Initiative for COPD (GOLD) guidelines outline a systematic approach to treating COPD involving an assessment on the severity of symptoms, the risk factors for future exacerbations, and the overall lung function. Beta-2 agonists are once again at the forefront of treatment options. In the case of COPD management per GOLD guidelines, anticholinergics are also often added on early along with beta-2 agonists and inhaled corticosteroids.[16]

Other Issues

Within the last few decades, the benefits of beta-2 agonists on the overall effect against mortality and morbidity have been a widely debated topic of discussion. While LABAs have been proven to improve pulmonary function, provide symptomatic relief, and improve quality of life,[17] there has been data suggesting the chronic use of LABAs as a monotherapy approach has led to an overall increase in severe asthma incidences leading up to hospitalization, intubation, or even mortality.[18] Subsequent studies were performed using dual therapy of LABAs and ICS as a treatment for asthma, and, compared to monotherapy, there was a decrease in the incidence of severe asthma exacerbations.[4] Current literature continues to support the safety of dual therapy versus monotherapy. In 2017, the FDA approved of the safety of dual therapy in asthmatic patients while warning against the use of monotherapy of LABAs. The Global Initiative for COPD and National Asthma Education and Prevention as well as many other guidelines which are in agreement of dual therapy to treat cases of asthma uncontrolled with SABA. Despite the support, it is still unclear on whether dual therapy can provide complete protection against the risk of asthma exacerbations that has been associated with single LABA treatment.

The topic of SABA overuse in previously clinically stable COPD patients is a point of discussion as studies have demonstrated without conclusive evidence a worsening of disease severity in this setting. An increase in airway hyperreactivity seems to occur with frequent, consistent usage of SABAs, which potentially lead to paradoxical airway narrowing.[7] SABA overuse is relatively prevalent in the population of asthma and COPD patients. In a study on COPD patients currently on treatment, 19% were overusing SABAs, and a separate study on asthmatic patients showed 15.8% overuse of SABAs. In the case of COPD patients, there was an association with increased dyspnea and worsening of quality of life.[19] However, further investigation is necessary before making a definitive statement.

Enhancing Healthcare Team Outcomes

Given that most patients will be on lifetime treatment for COPD and severe asthma, managing the treatment with beta-2 agonists in the context of the National Asthma Education and Prevention and GOLD guidelines respectively require a patient-centered approach involving coordination between multidisciplinary systems. At the level of primary care, studies have shown improvement in the quality of diagnostic and guideline-oriented therapy approach in settings with a designated respiratory care specialist. Patient outcomes improved under more focused care in terms of overall decreases in symptoms and decreases in the usage of rescue inhalers. Patients also demonstrated proper inhaler technique more frequently compared to facilities without a respiratory care specialist, and the use of spirometry as a means of diagnosis was greater.[20] [Level III]

Patients are often from the geriatric population, and coordination between the provider and a nursing home or community center is required to ensure medication compliance and adequate outpatient care, particularly in patients with multiple disabilities. Pulmonary rehabilitation, to regain lost strength and endurance as well as become reintegrated into the community, have shown improvements to the overall patient quality of life. This approach involves proper patient education on coping mechanisms for exacerbations or dyspnea to minimize emotional stress, on proper breathing techniques, the importance of pacing and life modifications, as well as muscle training. Communication with the patient on correct inhalation techniques, signs of adverse side effects, and lifestyle modifications, including the cessation of smoking can improve patient outcomes as well (Evidence level III).[20] Consultation with a pulmonologist and respiratory therapist are often involved in the medical management of the patient, especially in patients with multiple comorbidities.

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